Delivery of sedative-hypnotics through an inhalation route

ABSTRACT

The present invention relates to the delivery of sedative-hypnotics through an inhalation route. Specifically, it relates to aerosols containing sedative-hypnotics that are used in inhalation therapy. In a method aspect of the present invention, a sedative-hypnotic drug is administered to a patient through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises a sedative-hypnotic, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles with less than 5% sedative-hypnotic drug degradation products. In a kit aspect of the present invention, a kit for delivering a sedative-hypnotic through an inhalation route is provided which comprises: a) a thin coating of a sedative-hypnotic drug composition and b) a device for dispensing said thin coating as a condensation aerosol.

This application is a continuation of U.S. patent application Ser. No.10/150,857, entitled “Delivery of Sedative-Hypnotics Through anInhalation Route,” filed May 17, 2002, now U.S. Pat. No. 6,716,415,Rabinowitz and Zaffaroni, which claims priority to U.S. provisionalapplication Ser. No. 60/294,203 entitled “Thermal Vapor Delivery ofDrugs,” filed May 24, 2001, Rabinowitz and Zaffaroni and to U.S.provisional application Ser. No. 60/317,479 entitled “Aerosol DrugDelivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni, the entiredisclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the delivery of sedative-hypnoticsthrough an inhalation route. Specifically, it relates to aerosolscontaining sedative-hypnotics that are used in inhalation therapy.

BACKGROUND OF THE INVENTION

There are a number of compositions currently marketed assedative-hypnotics. The compositions contain at least one activeingredient that provides for observed therapeutic effects. Among theactive ingredients given in sedative-hypnotic compositions are zolpidem,zaleplon, and zopiclone.

It is desirable to provide a new route of administration forsedative-hypnotics that rapidly produces peak plasma concentrations ofthe compound. The provision of such a route is an object of the presentinvention.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of sedative-hypnoticsthrough an inhalation route. Specifically, it relates to aerosolscontaining sedative-hypnotics that are used in inhalation therapy.

In a composition aspect of the present invention, the aerosol comprisesparticles comprising at least 5 percent by weight of asedative-hypnotic. Preferably, the particles comprise at least 10percent by weight of a sedative hypnotic. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent or 99.97 percent by weight of a sedative hypnotic.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofsedative-hypnotic degradation products. Preferably, the particlescomprise less than 5 percent by weight of sedative-hypnotic degradationproducts. More preferably, the particles comprise less than 2.5, 1, 0.5,0.1 or 0.03 percent by weight of sedative-hypnotic degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

Typically, the aerosol is formed by heating a composition containing asedative-hypnotic to form a vapor and subsequently allowing the vapor tocondense into an aerosol.

In another composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight of zaleplon,zolpidem or zopiclone. Preferably, the particles comprise at least 10percent by weight of zaleplon, zolpidem or zopiclone. More preferably,the particles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent or 99.97 percent by weight ofzaleplon, zolpidem or zopiclone.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofzaleplon, zolpidem or zopiclone degradation products. Preferably, theparticles comprise less than 5 percent by weight of zaleplon, zolpidemor zopiclone degradation products. More preferably, the particlescomprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight ofzaleplon, zolpidem or zopiclone degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the aerosol has an inhalable aerosol drug mass density ofbetween 0.5 mg/L and 40 mg/L. Preferably, the aerosol has an inhalableaerosol drug mass density of between 1 mg/L and 20 mg/L. Morepreferably, the aerosol has an inhalable aerosol drug mass density ofbetween 1 mg/L and 10 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

Typically, the aerosol is formed by heating a composition containingzaleplon, zolpidem or zopiclone to form a vapor and subsequentlyallowing the vapor to condense into an aerosol.

In a method aspect of the present invention, one of a sedative-hypnoticis delivered to a mammal through an inhalation route. The methodcomprises: a) heating a composition, wherein the composition comprisesat least 5 percent by weight of a sedative-hypnotic, to form a vapor;and, b) allowing the vapor to cool, thereby forming a condensationaerosol comprising particles, which is inhaled by the mammal.Preferably, the composition that is heated comprises at least 10 percentby weight of a sedative-hypnotic. More preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of asedative-hypnotic.

Typically, the particles comprise at least 5 percent by weight of asedative-hypnotic. Preferably, the particles comprise at least 10percent by weight of a sedative-hypnotic. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of asedative-hypnotic.

Typically, the condensation aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofsedative-hypnotic degradation products. Preferably, the particlescomprise less than 5 percent by weight of sedative-hypnotic degradationproducts. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or0.03 percent by weight of sedative-hypnotic degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s). In certain embodiments theparticles have an MMAD of from about 0.2 to about 3 microns.

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhaleableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhaleable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of a sedative-hypnotic in the mammal in less than 1 h.Preferably, the peak plasma concentration is reached in less than 0.5 h.More preferably, the peak plasma concentration is reached in less than0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

Typically, the delivered condensation aerosol is used to treat insomnia.

In another method aspect of the present invention, one of zaleplon,zolpidem or zopiclone is delivered to a mammal through an inhalationroute. The method comprises: a) heating a composition, wherein thecomposition comprises at least 5 percent by weight of zaleplon, zolpidemor zopiclone, to form a vapor; and, b) allowing the vapor to cool,thereby forming a condensation aerosol comprising particles, which isinhaled by the mammal. Preferably, the composition that is heatedcomprises at least 10 percent by weight of zaleplon, zolpidem orzopiclone. More preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of zaleplon, zolpidem orzopiclone.

Typically, the particles comprise at least 5 percent by weight ofzaleplon, zolpidem or zopiclone. Preferably, the particles comprise atleast 10 percent by weight of zaleplon, zolpidem or zopiclone. Morepreferably, the particles comprise at least 20 percent, 30 percent, 40percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97percent by weight of zaleplon, zolpidem or zopiclone.

Typically, the condensation aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofzaleplon, zolpidem or zopiclone degradation products. Preferably, theparticles comprise less than 5 percent by weight of zaleplon, zolpidemor zopiclone degradation products. More preferably, the particlescomprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of zaleplon,zolpidem or zopiclone degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is amorphous in form.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

Typically, the delivered aerosol has an inhalable aerosol drug massdensity of between 0.5 mg/L and 40 mg/L. Preferably, the aerosol has aninhalable aerosol drug mass density of between 1 mg/L and 20 mg/L. Morepreferably, the aerosol has an inhalable aerosol drug mass density ofbetween 1 mg/L and 10 mg/L.

More preferably, the aerosol has an inhalable aerosol drug mass densityof between 1.5 mg/L and 7.5 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhaleableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhaleable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, between 0.5 mg and 40 mg of drug are delivered to the mammalin a single inspiration. Preferably, between 1 mg and 20 mg of drug aredelivered to the mammal in a single inspiration. More preferably,between 1 mg and 10 mg of drug are delivered to the mammal in a singleinspiration.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of zaleplon, zolpidem or zopiclone in the mammal in lessthan 1 h. Preferably, the peak plasma concentration is reached in lessthan 0.5 h. More preferably, the peak plasma concentration is reached inless than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

Typically, the delivered condensation aerosol is used to treat insomnia.

In a kit aspect of the present invention, a kit for delivering asedative-hypnotic through an inhalation route to a mammal is providedwhich comprises: a) a composition comprising at least 5 percent byweight of a sedative-hypnotic; and, b) a device that forms asedative-hypnotic aerosol from the composition, for inhalation by themammal. Preferably, the composition comprises at least 20 percent, 30percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percentor 99.97 percent by weight of a sedative-hypnotic.

Typically, the device contained in the kit comprises: a) an element forheating the sedative-hypnotic composition to form a vapor; b) an elementallowing the vapor to cool to form an aerosol; and, c) an elementpermitting the mammal to inhale the aerosol.

In another kit aspect of the present invention, a kit for deliveringzaleplon, zolpidem or zopiclone through an inhalation route to a mammalis provided which comprises: a) a composition comprising at least 5percent by weight of zaleplon, zolpidem or zopiclone; and, b) a devicethat forms a zaleplon, zolpidem or zopiclone aerosol from thecomposition, for inhalation by the mammal. Preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight ofzaleplon, zolpidem or zopiclone.

Typically, the device contained in the kit comprises: a) an element forheating the zaleplon, zolpidem or zopiclone composition to form a vapor;b) an element allowing the vapor to cool to form an aerosol; and, c) anelement permitting the mammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a cross-sectional view of a device used to deliversedative-hypnotic aerosols to a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Aerosol drug mass density” refers to the mass of sedative-hypnotic perunit volume of aerosol.

“Aerosol mass density” refers to the mass of particulate matter per unitvolume of aerosol.

“Aerosol particle density” refers to the number of particles per unitvolume of aerosol.

“Amorphous particle” refers to a particle that does not contain morethan 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

“Condensation aerosol” refers to an aerosol formed by vaporization of asubstance followed by condensation of the substance into an aerosol.

“Inhalable aerosol drug mass density” refers to the aerosol drug massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

“Inhalable aerosol mass density” refers to the aerosol mass densityproduced by an inhalation device and delivered into a typical patienttidal volume.

“Inhalable aerosol particle density” refers to the aerosol particledensity of particles of size between 100 nm and 5 microns produced by aninhalation device and delivered into a typical patient tidal volume.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

“Rate of inhalable aerosol particle formation” refers to the number ofparticles of size between 100 nm and 5 microns produced by an inhalationdevice per unit time.

“Rate of drug aerosol formation” refers to the mass of aerosolizedsedative-hypnotic produced by an inhalation device per unit time.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Sedative-hypnotic degradation product” refers to a compound resultingfrom a chemical modification of a sedative-hypnotic. The modification,for example, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

“Zaleplon” refers toN[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide,which is a free base.

“Zaleplon” degradation product refers to a compound resulting from achemical modification of zaleplon. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation products is C₁₃H₉N₅ (de-ethylation andde-amidation to provide unsubstituted aniline moiety).

“Zolpidem” refers toN,N,6-trimethyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-acetamide, which is afree base.

“Zolpidem” degradation product refers to a compound resulting from achemical modification of zolpidem. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is C₁₆H₁₄N₂O (amide removal).

“Zopiclone” refers to 4-methyl-1-piperazinecarboxylic acid6-[5-chloro-2-pyridinyl]-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-ylester.

“Zolpiclone” degradation product refers to a compound resulting from achemical modification of zopiclone. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.Examples of degradation products include 2-amino-5-chloropyridine and1-methyl piperazine.

Formation of Sedative-Hypnotic Containing Aerosols

Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising a sedative-hypnotic to form a vapor, followed by cooling ofthe vapor such that it condenses to provide a sedative-hypnoticcomprising aerosol (condensation aerosol). The composition is heated inone of four forms: as pure active compound (i.e., pure zaleplon,zolpidem or zopiclone); as a mixture of active compound and apharmaceutically acceptable excipient; as a salt form of the pure activecompound; and, as a mixture of active compound salt form and apharmaceutically acceptable excipient.

Salt forms of sedative-hypnotics (e.g., zaleplon, zolpidem or zopiclone)are either commercially available or are obtained from the correspondingfree base using well known methods in the art. A variety ofpharmaceutically acceptable salts are suitable for aerosolization. Suchsalts include, without limitation, the following: hydrochloric acid,hydrobromic acid, acetic acid, maleic acid, formic acid, and fumaricacid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile.Volatile excipients, when heated, are concurrently volatilized,aerosolized and inhaled with the sedative-hypnotic. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

Solid supports on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, solid supports provide a large surface to volumeratio (e.g., greater than 100 per meter) and a large surface to massratio (e.g., greater than 1 cm² per gram).

A solid support of one shape can also be transformed into another shapewith different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitablematerial. Examples of silica, alumina and silicon based materialsinclude amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (analumina of defined surface area greater than 2 m²/g from Aldrich, St.Louis, Mo.) and a silicon wafer as used in the semiconductor industry.Carbon yarns and felts are available from American Kynol, Inc., NewYork, N.Y. Chromatography resins such as octadecycl silane chemicallybonded to porous silica are exemplary coated variants of silica.

The heating of the sedative-hypnotic compositions is performed using anysuitable method. Examples of methods by which heat can be generatedinclude the following: passage of current through an electricalresistance element; absorption of electromagnetic radiation, such asmicrowave or laser light; and, exothermic chemical reactions, such asexothermic solvation, hydration of pyrophoric materials and oxidation ofcombustible materials.

Delivery of Sedative-Hypnotic Containing Aerosols

Sedative-hypnotic containing aerosols of the present invention aredelivered to a mammal using an inhalation device. Where the aerosol is acondensation aerosol, the device has at least three elements: an elementfor heating a sedative-hypnotic containing composition to form a vapor;an element allowing the vapor to cool, thereby providing a condensationaerosol; and, an element permitting the mammal to inhale the aerosol.Various suitable heating methods are described above. The element thatallows cooling is, in it simplest form, an inert passageway linking theheating means to the inhalation means. The element permitting inhalationis an aerosol exit portal that forms a connection between the coolingelement and the mammal's respiratory system.

One device used to deliver the sedative-hypnotic containing aerosol isdescribed in reference to FIG. 1. Delivery device 100 has a proximal end102 and a distal end 104, a heating module 106, a power source 108, anda mouthpiece 110. A sedative-hypnotic composition is deposited on asurface 112 of heating module 106. Upon activation of a user activatedswitch 114, power source 108 initiates heating of heating module 106(e.g, through ignition of combustible fuel or passage of current througha resistive heating element). The sedative-hypnotic compositionvolatilizes due to the heating of heating module 106 and condenses toform a condensation aerosol prior to reaching the mouthpiece 110 at theproximal end of the device 102. Air flow traveling from the devicedistal end 104 to the mouthpiece 110 carries the condensation aerosol tothe mouthpiece 110, where it is inhaled by the mammal.

Devices, if desired, contain a variety of components to facilitate thedelivery of sedative-hypnotic containing aerosols. For instance, thedevice may include any component known in the art to control the timingof drug aerosolization relative to inhalation (e.g., breath-actuation),to provide feedback to patients on the rate and/or volume of inhalation,to prevent excessive use (i.e., “lock-out” feature), to prevent use byunauthorized individuals, and/or to record dosing histories.

Dosage of Sedative-Hypnotic Containing Aerosols

The dosage amount of sedative-hypnotics in aerosol form is generally nogreater than twice the standard dose of the drug given orally. Forinstance, zaleplon, zolpidem and zopiclone are given orally at strengthsof 5 mg or 10 mg for the treatment of insomnia. As aerosols, 0.5 mg to40 mg of the compounds are generally provided per inspiration for thesame indication. A typical dosage of a sedative-hypnotic aerosol iseither administered as a single inhalation or as a series of inhalationstaken within an hour or less (dosage equals sum of inhaled amounts).Where the drug is administered as a series of inhalations, a differentamount may be delivered in each inhalation.

One can determine the appropriate dose of sedative-hypnotic containingaerosols to treat a particular condition using methods such as animalexperiments and a dose-finding (Phase I/II) clinical trial. One animalexperiment involves measuring plasma concentrations of drug in an animalafter its exposure to the aerosol. Mammals such as dogs or primates aretypically used in such studies, since their respiratory systems aresimilar to that of a human. Initial dose levels for testing in humans isgenerally less than or equal to the dose in the mammal model thatresulted in plasma drug levels associated with a therapeutic effect inhumans. Dose escalation in humans is then performed, until either anoptimal therapeutic response is obtained or a dose-limiting toxicity isencountered.

Analysis of Sedative-Hypnotic Containing Aerosols

Purity of a sedative-hypnotic containing aerosol is determined using anumber of methods, examples of which are described in Sekine et al.,Journal of Forensic Science 32:1271–1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158–162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detectionsystem (i.e., detector). Such detection systems are well known in theart and include, for example, flame ionization, photon absorption andmass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure ofsedative-hypnotic degradation products.

Particle size distribution of a sedative-hypnotic containing aerosol isdetermined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

Inhalable aerosol mass density is determined, for example, by deliveringa drug-containing aerosol into a confined chamber via an inhalationdevice and measuring the mass collected in the chamber. Typically, theaerosol is drawn into the chamber by having a pressure gradient betweenthe device and the chamber, wherein the chamber is at lower pressurethan the device. The volume of the chamber should approximate the tidalvolume of an inhaling patient.

Inhalable aerosol drug mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation is determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation is determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation is determined, for example, by deliveringa sedative-hypnotic containing aerosol into a confined chamber via aninhalation device over a set period of time (e.g., 3 s). Where theaerosol is pure sedative-hypnotic, the amount of drug collected in thechamber is measured as described above. The rate of drug aerosolformation is equal to the amount of sedative-hypnotic collected in thechamber divided by the duration of the collection time. Where thesedative-hypnotic containing aerosol comprises a pharmaceuticallyacceptable excipient, multiplying the rate of aerosol formation by thepercentage of sedative-hypnotic in the aerosol provides the rate of drugaerosol formation.

Utility of Sedative-Hypnotic Containing Aerosols

The sedative-hypnotic containing aerosols of the present invention aretypically used for the treatment of insomnia. Other uses for theaerosols include, without limitation, the following: an anticonvulsant;an anxiolytic; and, a myorelaxant.

The following examples are meant to illustrate, rather than limit, thepresent invention.

Zolpidem and zopiclone are commercially available from Sigma(www.sigma-aldrich.com). Zaleplon is available in capsule form (SONATA®)and can be isolated using standard methods in the art.

EXAMPLE 1 Volatilization of Zaleplon

A solution of 5.5 mg zaleplon in approximately 120 μL dichloromethanewas coated on a 3 cm×8 cm piece of aluminum foil. The dichloromethanewas allowed to evaporate. Assuming a drug density of about 1 g/cc, thecalculated thickness of the zaleplon coating on the 24 cm² aluminumsolid support, after solvent evaporation, is about 2.3 microns. Thecoated foil was wrapped around a 300 watt halogen tube (Feit ElectricCompany, Pico Rivera, Calif.), which was inserted into a glass tubesealed at one end with a rubber stopper. Running 60 V of alternatingcurrent (driven by line power controlled by a variac) through the bulbfor 7 s afforded zaleplon thermal vapor (including zaleplon aerosol),which collected on the glass tube walls. Reverse-phase HPLC analysiswith detection by absorption of 225 nm light showed the collectedmaterial to be greater than 99% pure zaleplon.

EXAMPLE 2 Volatilization of Zolpidem

A solution of 5.3 mg zolpidem in approximately 120 μL dichloromethanewas coated on a 3 cm×8 cm piece of aluminum foil. The dichloromethanewas allowed to evaporate. Assuming a drug density of about 1 g/cc, thecalculated thickness of the zolpidem coating on the 24 cm² aluminumsolid support, after solvent evaporation, is about 2.3 microns. Thecoated foil was wrapped around a 300 watt halogen tube (Feit ElectricCompany, Pico Rivera, Calif.), which was inserted into a glass tubesealed at one end with a rubber stopper. Running 60 V of alternatingcurrent (driven by line power controlled by a variac) through the bulbfor 6 s afforded zolpidem thermal vapor (including zolpidem aerosol),which collected on the glass tube walls. Reverse-phase HPLC analysiswith detection by absorption of 225 nm light showed the collectedmaterial to be greater than 99% pure zolpidem.

EXAMPLE 3 Volatilization of Zopiclone

A solution of 3.5 mg zopiclone in approximately 120 μL dichloromethanewas coated on a 3 cm×8 cm piece of aluminum foil. The dichloromethanewas allowed to evaporate. Assuming a drug density of about 1 g/cc. thecalculated thickness of the zopiclone coating on the 24 cm² aluminumsolid support, after solvent evaporation, is about 1.5 microns. Thecoated foil was wrapped around a 300 watt halogen tube (Feit ElectricCompany, Pico Rivera, Calif.), which was inserted into a glass tubesealed at one end with a rubber stopper. Running 60 V of alternatingcurrent (driven by line power controlled by a variac) through the bulbfor 6 s afforded zopiclone thermal vapor (including zopiclone aerosol),which collected on the glass tube walls. Reverse-phase HPLC analysiswith detection by absorption of 225 nm light showed the collectedmaterial to be greater than 99% pure zopiclone.

EXAMPLE 4 Particle Size, Particle Density, and Rate of InhalableParticleFormation of Zolpidem Aerosol

A solution of 10.7 mg zolpidem in 100 μL dichloromethane was spread outin a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Assuming adrug density of about 1 g/cc, the calculated thickness of the zolpidemcoating on the 24.5 cm² aluminum solid support, after solventevaporation, is about 4.4 microns. The aluminum foil was wrapped arounda 300 watt halogen tube, which was inserted into a T-shaped glass tube.Both of the openings of the tube were sealed with parafilm, which waspunctured with fifteen needles for air flow. The third opening wasconnected to a 1 liter, 3-neck glass flask. The glass flask was furtherconnected to a large piston capable of drawing 1.1 liters of air throughthe flask. Alternating current was run through the halogen bulb byapplication of 90 V using a variac connected to 110 V line power. Within1 s, an aerosol appeared and was drawn into the 1 L flask by use of thepiston, with collection of the aerosol terminated after 6 s. The aerosolwas analyzed by connecting the 1 L flask to an eight-stage Andersennon-viable cascade impactor. Results are shown in table 1. MMAD of thecollected aerosol was 2.9 microns with a geometric standard deviation of2.1. Also shown in table 1 is the number of particles collected on thevarious stages of the cascade impactor, given by the mass collected onthe stage divided by the mass of a typical particle trapped on thatstage. The mass of a single particle of diameter D is given by thevolume of the particle, πD³/6, multiplied by the density of the drug(taken to be 1 g/cm³). The inhalable aerosol particle density is the sumof the numbers of particles collected on impactor stages 3 to 8 dividedby the collection volume of 1 L, giving an inhalable aerosol particledensity of 3.9×10⁶ particles/mL. The rate of inhalable aerosol particleformation is the sum of the numbers of particles collected on impactorstages 3 through 8 divided by the formation time of 6 s, giving a rateof inhalable aerosol particle formation of 6.4×10⁸ particles/second.

EXAMPLE 5 Drug Mass Density and Rate of Drug Aerosol Formation ofZolpidem Aerosol

A solution of 8.3 mg zolpidem in 100 μL dichloromethane was spread outin a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Assuming adrug density of about 1 g/cc. the calculated thickness of the zolpidemcoating on the 24.5 cm² aluminum solid support, after solventevaporation, is about 3.4 microns. The aluminum foil was wrapped arounda 300 watt halogen tube, which was inserted into a T-shaped glass tube.Both of the openings of the tube were sealed with parafilm, which waspunctured with fifteen needles for air flow. The third opening wasconnected to a 1 liter, 3-neck glass flask. The glass flask was furtherconnected to a large piston capable of drawing 1.1 liters of air throughthe flask. Alternating current was run through the halogen bulb byapplication of 90 V using a variac connected to 110 V line power. Withinseconds, an aerosol appeared and was drawn into the 1 L flask by use ofthe piston, with formation of the aerosol terminated after 6 s. Theaerosol was allowed to sediment onto the walls of the 1 L flask forapproximately 30 minutes. The flask was then extracted with acetonitrileand the extract analyzed by HIPLC with detection by light absorption at225 nm. Comparison with standards containing known amounts of zolpidemrevealed that 3.7 mg of >97% pure zolpidem had been collected in theflask, resulting in an aerosol drug mass density of 3.7 mg/L. Thealuminum foil upon which the zolpidem had previously been coated wasweighed following the experiment. Of the 8.3 mg originally coated on thealuminum, 7.4 mg of the material was found to have aerosolized in the 6s time period, implying a rate of drug aerosol formation of 1.2 mg/s.

TABLE 1 Determination of the characteristics of a zolpidem condensationaerosol by cascade impaction using an Andersen 8-stage non-viablecascade impactor run at 1 cubic foot per minute air flow. Mass Particlesize Average particle collected Number of Stage range (microns) size(microns) (mg) particles 0  9.0–10.0 9.5 0.1 2.2 × 10⁵ 1 5.8–9.0 7.4 0.31.4 × 10⁶ 2 4.7–5.8 5.25 0.4 5.3 × 10⁶ 3 3.3–4.7 4.0 0.9 2.7 × 10⁷ 42.1–3.3 2.7 1.1 1.1 × 10⁸ 5 1.1–2.1 1.6 0.8 3.7 × 10⁸ 6 0.7–1.1 0.9 0.41.1 × 10⁹ 7 0.4–0.7 0.55 0.2 2.3 × 10⁹ 8   0–0.4 0.2 0.0 0

1. A method of treating insomnia in a patient comprising administering atherapeutic amount of a drug condensation aerosol to the patient byinhalation, wherein the drug is selected from the group consisting ofzaleplon, zolpidem and zopiclone, and wherein the condensation aerosolis formed by heating a thin layer containing the drug, on a solidsupport, to produce a vapor of the drug, and condensing the vapor toform a condensation aerosol characterized by less than 10% drugdegradation products by weight, and an MMAD of less than 5 microns. 2.The method according to claim 1, wherein the condensation aerosol ischaracterized by an MMAD of less than 3 microns.
 3. The method accordingto claim 1, wherein peak plasma drug concentration is reached in lessthan 0.1 hours.
 4. The method according to claim 1, wherein thecondensation aerosol is formed at a rate greater than 0.5 mg/second. 5.The method according to claim 1, wherein at least 50% by weight of thecondensation aerosol is amorphous in form.
 6. A method of administeringa drug condensation aerosol to a patient comprising administering thedrug condensation aerosol to the patient by inhalation, wherein the drugis selected from the group consisting of zaleplon, zolpidem andzopiclone, and wherein the drug condensation aerosol is formed byheating a thin layer containing the drug, on a solid support, to producea vapor of the drug, and condensing the vapor to form a condensationaerosol characterized by less than 10% drug degradation products byweight, and an MMAD of less than 5 microns.
 7. A kit for delivering adrug condensation aerosol comprising: a. a thin layer containing thedrug, on a solid support, wherein the drug is selected from the groupconsisting of zaleplon, zolpidem and zopiclone, and b. a device forproviding the condensation aerosol, wherein the condensation aerosol isformed by heating the thin layer to produce a vapor of the drug, andcondensing the vapor to form a condensation aerosol characterized byless than 10% drug degradation products by weight, and an MMAD of lessthan 5 microns.
 8. The kit according to claim 7, wherein the devicecomprises: a. a flow through enclosure containing the solid support, b.a power source that can be activated to heat the solid support, and c.at least one portal through which air can be drawn by inhalation,wherein activation of the power source is effective to produce a vaporof the drug, and drawing air through the enclosure is effective tocondense the vapor to form the condensation aerosol.
 9. The kitaccording to claim 8, wherein the heat for heating the solid support isgenerated by an exothermic chemical reaction.
 10. The kit according toclaim 9, wherein the exothermic chemical reaction is oxidation ofcombustible materials.
 11. The kit according to claim 8, wherein theheat for heating the solid support is generated by passage of currentthrough an electrical resistance element.
 12. The kit according to claim8, wherein the solid support has a surface area dimensioned toaccommodate a therapeutic dose of the drug.
 13. The kit according toclaim 7, wherein peak plasma drug concentration is reached in less than0.1 hours.
 14. The kit according to claim 7, further includinginstructions for use.
 15. The method according to claim 1, wherein thetherapeutic amount of a drug condensation aerosol comprises between 0.5mg and 40 mg of zaleplon delivered in a single inspiration.
 16. Themethod according to claim 1, wherein the therapeutic amount of a drugcondensation aerosol comprises between 0.5 mg and 40 mg of zolpidemdelivered in a single inspiration.
 17. The method according to claim 1,wherein the therapeutic amount of a drug condensation aerosol comprisesbetween 0.5 mg and 40 mg of zopiclone delivered in a single inspiration.18. The method according to claim 1, wherein the condensation aerosol ischaracterized by an MMAD of 0.1 to 3 microns.
 19. The method accordingto claim 1, wherein the condensation aerosol is characterized by an MMADof about 0.2 to about 3 microns.
 20. The method according to claim 1,wherein the thin layer has a thickness between 1.5 and 4.4 microns. 21.The method according to claim 6, wherein the drug is zaleplon.
 22. Themethod according to claim 6, wherein the drug is zolpidem.
 23. Themethod according to claim 6, wherein the drug is zopiclone.
 24. The kitaccording to claim 7, wherein the condensation aerosol is characterizedby an MMAD of less than 3 microns.
 25. The kit according to claim 7wherein the condensation aerosol is characterized by an MMAD of 0.1 to 5microns.
 26. The kit according to claim 7, wherein the condensationaerosol is characterized by an MMAD of about 0.2 to about 3 microns. 27.The kit according to claim 7, wherein the thin layer has a thicknessbetween 1.5 and 4.4 microns.
 28. The kit according to claim 7, whereinthe drug is zaleplon.
 29. The kit according to claim 7, wherein the drugis zolpidem.
 30. The kit according to claim 7, wherein the drug iszopiclone.
 31. The kit according to claim 8, wherein the solid supporthas a surface to mass ratio of greater than 1 cm² per gram.
 32. The kitaccording to claim 8, wherein the solid support has a surface to volumeratio of greater than 100 per meter.
 33. The kit according to claim 8,wherein the solid support is a metal foil.
 34. The kit according toclaim 33, wherein the metal foil has a thickness of less than 0.25 mm.